★阿修羅♪ > 不安と不健康18 > 285.html
 ★阿修羅♪  
▲コメTop ▼コメBtm 次へ 前へ
幹線道路沿いに居住で認知症リスク高まる=調査 Living near major roads and dementia 
http://www.asyura2.com/16/health18/msg/285.html
投稿者 軽毛 日時 2017 年 1 月 06 日 18:33:21: pa/Xvdnb8K3Zc jHmW0Q
 

幹線道路沿いに居住で認知症リスク高まる=調査
2017/01/05
BBC News

ジェイムズ・ギャラガー科学ヘルス担当記者

カナダで実施された大規模調査で、幹線道路の近くに住むと認知症のリスクが高まるとの結果が出た。研究結果は英医学誌「ランセット」に掲載された。

主要な道路から50メートル以内に住む人が認知症を発症したケースで、その約1割は、交通量の多さが原因になっていると、研究は示唆している。

英国の認知症の専門家は、さらに研究を進める必要があると指摘したが、研究結果は「あり得る」と評価した。

世界の認知症の患者数は5000万人近くに上る。認知症の原因は特定されていない。

人口増加

研究は、カナダのオンタリオ州で2001年から12年にかけ、200万人近くのデータを使用した。

期間中に認知症の診断を受けた24万3611人のデータを調べたところ、幹線道路から300メートル以上離れた場所に住んでいる人に比べて、101〜200メートルでは発症リスクが2%高まり、50〜100メートルは4%上昇した。50メートル以内では、リスクは7%高かった。

分析の結果、幹線道路から50メートル以内に住む人の認知症の7〜11%が、交通量の多さに関係しているとみられるという。

研究論文の執筆者の1人、オンタリオ州の公衆衛生に関する助言機関「パブリック・ヘルス・オンタリオ」のホン・チェン博士は、「人口増加の加速と都市化によって、多くの人々が交通量の多い場所に住むようになっている。交通の影響にさらされる人が増加し、認知症の発症率が上昇するなか、道路の近くに住むことの影響は、例え軽微だったとしても、保健行政にとって大きな負担となる可能性がある」と語った。

チェン氏は、「関連を理解するにはさらに研究が必要で、特に大気汚染物質や騒音といった交通のさまざまな側面による影響を調べる必要がある」と述べた。

研究者たちは、騒音や微小粒子状物質、窒素酸化物やタイヤの摩耗から出る粒子が関係している可能性を指摘している。

しかし研究では、認知症と診断された人がどこに住んでいるのかのみに焦点を当てており、交通量の多さと認知症との因果関係は証明されていない。

刺激的

英国立衛生研究所(NIHR)で認知症研究を率いるマーティン・ロッソ―教授は、「これは重要な論文だ」と話す。「(幹線道路からの距離による)影響は小さいが、人口当たりの発症率が高い疾病なだけに、公衆衛生にとって大きな意味を持つかもしれない」。

英ノッティンガム大学の認知症センター長、トム・デニング氏は研究結果について、「興味深く、刺激的」だと述べ、「排気ガスが脳疾患に影響を及ぼし、時間の経過と共に認知症リスクを高めるというのは確かに納得がいく。今回の論証はまた、交通量の多い場所に住む人々の不安を高めることになるだろう」と語った。

「深刻な大気汚染の中で生活するのは紛れもなく非常に不快なことで、誰にとっても良いこととは思えない」

認知症リスクを抑制するための一番良いアドバイスは、体に良いとされることを実践することだろう。喫煙をやめ、運動し、健康な食生活を心がけることだ。

(英語記事 Dementia rates 'higher near busy roads')

提供元:http://www.bbc.com/japanese/features-and-analysis-38515371


 

Living near major roads and the incidence of dementia, Parkinson's disease, and multiple sclerosis: a population-based cohort study

Hong Chen, PhDcorrespondencePress enter key for correspondence informationemailPress enter key to Email the author, Jeffrey C Kwong, MD, Ray Copes, MD, Karen Tu, MD, Paul J Villeneuve, PhD, Aaron van Donkelaar, PhD, Perry Hystad, PhD, Prof Randall V Martin, PhD, Brian J Murray, MD, Barry Jessiman, MSc, Andrew S Wilton, MSc, Alexander Kopp, BA, Richard T Burnett, PhD
Published: 04 January 2017
Article has an altmetric score of 1153
DOI: http://dx.doi.org/10.1016/S0140-6736(16)32399-6 |
showArticle Info
Summary
Full Text

Tables and Figures
References
Supplementary Material
Summary
Go
Background
Emerging evidence suggests that living near major roads might adversely affect cognition. However, little is known about its relationship with the incidence of dementia, Parkinson's disease, and multiple sclerosis. We aimed to investigate the association between residential proximity to major roadways and the incidence of these three neurological diseases in Ontario, Canada.

Methods
In this population-based cohort study, we assembled two population-based cohorts including all adults aged 20–50 years (about 4·4 million; multiple sclerosis cohort) and all adults aged 55–85 years (about 2·2 million; dementia or Parkinson's disease cohort) who resided in Ontario, Canada on April 1, 2001. Eligible patients were free of these neurological diseases, Ontario residents for 5 years or longer, and Canadian-born. We ascertained the individual's proximity to major roadways based on their residential postal-code address in 1996, 5 years before cohort inception. Incident diagnoses of dementia, Parkinson's disease, and multiple sclerosis were ascertained from provincial health administrative databases with validated algorithms. We assessed the associations between traffic proximity and incident dementia, Parkinson's disease, and multiple sclerosis using Cox proportional hazards models, adjusting for individual and contextual factors such as diabetes, brain injury, and neighbourhood income. We did various sensitivity analyses, such as adjusting for access to neurologists and exposure to selected air pollutants, and restricting to never movers and urban dwellers.

Findings
Between 2001, and 2012, we identified 243 611 incident cases of dementia, 31 577 cases of Parkinson's disease, and 9247 cases of multiple sclerosis. The adjusted hazard ratio (HR) of incident dementia was 1·07 for people living less than 50 m from a major traffic road (95% CI 1·06–1·08), 1·04 (1·02–1·05) for 50–100 m, 1·02 (1·01–1·03) for 101–200 m, and 1·00 (0·99–1·01) for 201–300 m versus further than 300 m (p for trend=0·0349). The associations were robust to sensitivity analyses and seemed stronger among urban residents, especially those who lived in major cities (HR 1·12, 95% CI 1·10–1·14 for people living <50 m from a major traffic road), and who never moved (1·12, 1·10–1·14 for people living <50 m from a major traffic road). No association was found with Parkinson's disease or multiple sclerosis.

Interpretation
In this large population-based cohort, living close to heavy traffic was associated with a higher incidence of dementia, but not with Parkinson's disease or multiple sclerosis.

Funding
Health Canada (MOA-4500314182).

Introduction
Go
Dementia, Parkinson's disease, and multiple sclerosis are among the most common neurodegenerative diseases, with devastating effects on individuals, families, and society. Globally, about 55 million people have these disorders, with rising numbers expected given increasing longevity.1, 2 Without cures, identification of modifiable risk factors is important.

Despite the mounting global effect of these neurodegenerative diseases, their cause remains largely unknown.3, 4, 5 Concern is growing that exposures associated with traffic such as air pollution and noise might con-tribute to neurodegenerative pathology.6, 7 Results of studies showed that air pollutants and diesel exhaust induce oxidative stress and neuroinflammation,8 activate microglia,9 and stimulate neural antibodies.10 Exposure to more noise also impairs cognitive abilities in rats.11 Similarly, a few epidemiologic studies12, 13, 14 linked traffic-related noise and air pollution to cognitive decline and increased incidence of Parkinson's disease15 and Alzheimer's disease.16 Traffic exposure might affect various neurodegenerative processes.

Studies also showed that living near roads was associated with reduced white matter hyperintensity volume17 and cognition,18, 19 but its effect on the incidence of dementia, Parkinson's disease, and multiple sclerosis is unknown. Living near traffic is a multifaceted exposure representing heightened exposure to nitrogen oxides, ultrafine particles, fine particulate matter (≤2·5 μm in diameter or PM2·5), heavy metals, polycyclic aromatic hydrocarbons, volatile organic compounds, noise, and other factors. Because hundreds of millions of people worldwide live close to major roads, we sought to investigate the association between exposure to traffic, measured by residential proximity to major roadways, and the incidence of dementia, Parkinson's disease, and multiple sclerosis in a large population-based cohort in Ontario, Canada.

Research in context


Evidence before this study
We searched the MEDLINE and Embase databases for epidemiological studies of the associations between exposure to roadway traffic and the risk in adults (older than 18 years of age) of developing dementia, Parkinson's disease, or multiple sclerosis. Studies published in the peer-review literature up to Feb 1, 2016, were included, regardless of the language of publication. We perused the bibliographies of these articles and of previously published reviews. We searched the bibliographic databases using the keywords traffic exposure, mobile source, roadway, proximity or near, air pollution, and with the following health outcomes: dementia; Alzheimer's disease; cognition; Parkinson's disease; multiple sclerosis. A few studies found an association between living close to major roadways and cognitive decline and changes in the brain structure. There is also some evidence linking traffic-related noise and air pollution to cognitive decline and the incidence of dementia, and to a lesser degree, Parkinson's disease. No study has so far investigated the onset of all three major neurodegenerative diseases (dementia, Parkinson's disease, and multiple sclerosis) in association with near-road exposure. Moreover, the few existing studies involved relatively small study populations and nearly half were cross-sectional.
Added value of this study
We report that living close to heavy traffic is associated with increased incidence of dementia. Using the same populations and methods, however, we did not find an association between residential proximity to traffic and Parkinson's disease or multiple sclerosis.
The cause of these major neurodegenerative diseases remains largely unclear. This study sheds important insights into a possible role of near-road exposure on the development of dementia. Our study overcomes several limitations of previous studies, since it has large cohorts comprising almost the entire adult population in Ontario, the most populous province in Canada, and lagged exposure up to 10 years to reduce concerns about reverse causality. With demographic characteristics similar to the USA and many European countries, findings from this study will be highly generalisable to populations in many other regions.
Implications of all the available evidence
Increasing population growth and continuing urbanisation globally has placed many people close to heavy traffic. With the widespread exposure to traffic and growing population with dementia, even a modest effect from near-road exposure can pose an enormous public health burden. This study suggests that improvements in environmental health policies and land use planning aimed at reducing traffic exposure can have considerable potential for prevention of dementia, which would lead to a broad public health implication. This study adds weight to previous observations suggesting that roadway traffic is an important source of environmental stressors that could give rise to neurological disorders and that future investigation targeting the effects of different aspects of traffic such as traffic-related air pollutants and noise on neurological health is merited.
Methods
Go
Study design
We did a population-based cohort study of all Ontario adults to determine the incidence of dementia, Parkinson's disease, and multiple sclerosis. Eligible participants were, as of April 1, 2001, Ontario residents for 5 years or longer, aged 20–85 years, and Canadian-born. We created the study population using Ontario's Registered Persons Database, a registry of all residents who have ever had health insurance. This database covers virtually all Ontario residents.20
Because dementia and Parkinson's disease onset occurs predominantly in people aged 55 years or older, whereas multiple sclerosis onset is most common in adults younger than 50 years, we separated the study population into two analytical cohorts: individuals aged 20–50 years (multiple sclerosis cohort); and individuals aged 55–85 years (dementia or Parkinson's disease cohort). We further excluded individuals with any of these three disorders at baseline, yielding a total of 4 372 720 and 2 165 268 participants in each cohort.

The Research Ethics Board of Sunnybrook Health Sciences Centre, Toronto, approved the study.

We ascertained incident diagnoses of dementia, Parkinson's disease, and multiple sclerosis using validated databases (see appendix). Details of these databases are available elsewhere.20 These databases have been validated previously using chart review, with sensitivity of 78–84% and specificity of 99–100%.21, 22, 23 They were created using hospital discharge abstracts from the Canadian Institute for Health Information, physician service claims from the Ontario Health Insurance Plan database, and prescription medication claims from the Ontario Drug Benefits programme database. Hospital, laboratory, and physician services in Ontario are funded by the provincial government through a single-payer universal medicare system that covers virtually all residents.20 Drug coverage is provided to those aged 65 years or older, and social assistance recipients. We linked the cohorts to these databases using encrypted unique identifiers to ascertain incident cases.

Residential proximity to roads
We calculated residential proximity to major roadways or highways based on 6-character postal-code addresses in 1996, 5 years before cohort inception. Postal codes in urban areas represent the centroid of the blocks or single large buildings in which cohort members lived. Distance (m) was measured using ArcGIS. Major traffic roads include primary urban roads and arterial roads (ie, a major thoroughfare with medium to large traffic capacity with a combination of controlled access and intersections at grade level) whereas highways include expressways and primary and secondary highways, according to Ontario Government Road Network Data Standards. Consistent with previous studies,17, 24 we created five distance categories: less than 50 m from major traffic road, 50–100 m, 101–200 m, 201–300 m, and more than 300 m. We also considered a continuous measure of distance.

Covariates
We selected accepted or suspected risk factors for neurodegenerative pathology, including age, sex, pre-existing comorbidities, and socioeconomic status.3, 4, 5 The comorbidities included traumatic brain injury, diabetes, hypertension, stroke, coronary heart disease, congestive heart failure, and arrhythmia. We ascertained the presence of comorbidities at baseline using hospital discharge abstracts, physician service claims, and validated chronic disease databases (appendix).

Several individual-level socioeconomic status and behavioural factors, such as education, smoking, and physical activity are also implicated in neurological health,3, 4, 5 but were unavailable. Since neighbourhood-level socioeconomic status is strongly associated with these factors,25, 26 we derived four neighbourhood-level variables: income quintile, a measure of relative household income accounting for household size and community; percentage of population aged 15 years or older with less than high school education; unemployment rate; and percentage of recent immigrants, using 2001 Canadian Census dissemination area data. A dissemination area (with 400–700 people) is the smallest census geographic area for which census data are disseminated. We further derived neighbourhood-level deprivation based on the Ontario Marginalization Index that quantifies the degree of marginalisation in health and social wellbeing (appendix).

To control for regional differences in the incidence of dementia, Parkinson's disease, and multiple sclerosis, we created a variable for urban residence (yes/no), density of neurologists using the ICES Physician Database to represent accessibility to neurological care, and the latitude of residence given the reported latitude gradient with multiple sclerosis.3 Additionally, we created a dichotomous variable classifying Ontario into the Greater Toronto Area, a densely-populated urban mega-region, and all other areas. Toronto tends to differ from other areas with respect to sociodemographic characteristics, health care access, and population health status.

To explore whether exposure to air pollutants, especially nitrogen dioxide (NO2) and PM2·5 might explain the roadway proximity-outcome association, we obtained long-term measures of PM2·5 and NO2 for all participants (appendix). Briefly, estimates of ground-level concentrations of PM2·5 were derived from satellite observations of aerosol optical depth in combination with outputs from a global atmospheric chemistry transport model (GEOS-Chem CTM).27 The PM2·5 estimates were further adjusted using information on urban land cover, elevation, and aerosol composition using a geographically weighted regression. We used estimates between 1998 (the earliest year with available data) and 2001 (the year of cohort inception), thus producing four-year mean concentration of PM2·5 at a spatial resolution of 1 × 1 km and covering all North America below 70°N, which includes all of Ontario. These satellite-based estimates of PM2·5 closely agree with ground measurements at fixed-site monitoring stations across North America (R2 0·82, n=1440).27 Similarly, we derived long-term exposure to NO2 from a national land-use regression (LUR) model developed from Environment Canada's National Air Pollution Surveillance Network monitoring data, 2005–11 satellite NO2 estimates, area of industrial land use, road length, and mean summer rain fall.28 The estimates were further calibrated by incorporating local-scale variations of NO2 from vehicle emissions by applying spatially-varying multipliers that represented distance-decay gradient in NO2. The final LUR model explained 73% of the variation in annual 2006 measurements of NO2, with a root mean square error of 2·9 parts per billion (ppb).28 The resulting LUR NO2 estimates were available for each year between 1998 and 2001, after applying temporal adjustment.

Statistical analysis
We used Cox proportional hazards models with age as the time-scale to assess the relationship between residential proximity to major roadways and the incidence of dementia, Parkinson's disease, and multiple sclerosis. For each outcome, follow up time (in days) was measured from April 1, 2001 until diagnosis date, ineligibility for provincial health insurance, death, or March 31, 2012.

Separate models were developed for each disease. All models were stratified by region (living in Toronto or not), and adjusted for sex, comorbidities, urban residency, and neighbourhood-level income, education, unemployment, and immigration status. To adjust for regional variations in the neighbourhood-level variables across Ontario, we included them as the average for each census division (equivalent to county), and as the difference between the values for each census dissemination area and the census division mean. We further adjusted for latitude for multiple sclerosis cohort. The analyses were repeated using distance as categorical and continuous variables.

We routinely tested for deviation from the pro-portional hazards assumption by adding the cross-product of each variable with the natural logarithm of the time variable, but we did not find any violation of this assumption (p>0·05). We calculated adjusted hazard ratios (HRs) and 95% CIs for each category of roadway proximity compared with the furthest category (>300 m). Linear trend was assessed by assigning the median distance (in natural log) to each category and fitting the term as a continuous variable in a regression model. In analyses with distance as a continuous variable, we considered the natural log of distance because this exposure has been linearly related to mortality and morbidity outcomes in Ontario and elsewhere.17, 24

Sensitivity analyses
We controlled for access to neurologists, deprivation index, and a North/South indicator (appendix). We also adjusted for a linear term for time to account for potential changes in the risk of the three disorders over time.

We assessed whether HR might be influenced by any spatial dependence among participants. We fitted models with a frailty term for census division (ie, county) to account for the possibility that participants in the same community could share similar risk factors than those living in different locations. We assumed a gamma distribution for the frailties, with an exchangeable correlation structure within county.

We assessed the potential influence of unmeasured individual-level socioeconomic status and behavioural variables, especially education, smoking, obesity, and physical activity on our results. To do this, we used a method to mathematically adjust HR for these variables while simultaneously controlling for all variables available in the model (ie, age, sex, comorbidities, and socioeconomic status; appendix). Details of this method are presented elsewhere.29 Briefly, this method requires spatial associations between the unmeasured and observed variables from an auxiliary dataset. Following previous Canadian studies,30 we obtained the relationships using data from the 1996–97 cycle of the National Population Health Survey and the 2000–01 and 2003 cycles of the Canadian Community Health Survey, which constituted a representative sample of the study cohorts (appendix). This information along with estimated associations between these unmeasured variables and incident dementia, Parkinson's disease, and multiple sclerosis from the literature, were used to estimate their effect on HR. Based on systematic reviews of dementia, Parkinson's disease, and multiple sclerosis, we considered all four variables in our analysis with dementia, smoking and physical activity with Parkinson's disease, and smoking with multiple sclerosis (appendix).

Furthermore, we additionally adjusted for PM2·5 and NO2, excluded events occurring in the first 2 and 5 years during follow-up to lag exposure up to 10 years, excluded people residing in long-term care facilities (often located near major roadways) at baseline, and restricted the dementia/Parkinson's disease cohort to those aged 65 years or older because drug information was unavailable for younger adults. Lastly, we further adjusted for rurality index and neighbourhood-level percentage of visible minority, and restricted the analysis to people who never moved since 1996, to urban residents, and to residents of six major urban centres in Ontario (Toronto, Hamilton, Ottawa, London, Windsor, and Sarnia) (appendix).

Role of the funding source
The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results
Go
The multiple sclerosis cohort comprised 46·7 million person-years of observations and the dementia/Parkinson's disease cohort contributed 20·1 million person-years. At baseline, the mean age was 35·9 years (SD 8·7 years) for the multiple sclerosis cohort and 66·8 years (8·2 years) for the dementia/Parkinson's disease cohort (table 1). Of the multiple sclerosis cohort, 50% were male, 17% were rural residents, 2% had diabetes, and 7% had hypertension, whereas 47% of the dementia/Parkinson's disease cohort were male, 19% were rural residents, 15% had diabetes, and 48% had hypertension. Average unemployment among census dissemination areas was 6% and the mean percentage of population with less than high school education was about 26% in both cohorts.

Table 1
Baseline characteristics of the study population

Table Thumbnail. Opens Table in new tab.

Data are n or %, unless otherwise specified.

*Multiple sclerosis cohort comprised all adults aged 20–50 years and dementia/Parkinson's disease cohort comprised all adults aged 55–85 years in Ontario, Canada, in 2001.
†In the 10 years before cohort onset.
‡From Canadian Census 2001, at the census dissemination area level.
Nearly half of the cohorts lived within 200 m from a major road and 95% were within 1000 m (appendix). Of the cohorts, the average concentration of PM2·5 according to participants' residences in 1996, 5 years before cohort inception, was 9·7 μg/m3 (range 1·3–19·8 μg/m3), while the average concentration of NO2 was 15·4 ppb (2·2–62·0 ppb). Between 2001–12, we identified 243 611 incident cases of dementia, 31 577 incident cases of Parkinson's disease, and 9247 incident cases of multiple sclerosis.

In both categorical and continuous analyses, living closer to a major road was associated with increased incidence of dementia, with fully adjusted HR of 1·07 (95% CI 1·06–1·08) for people living less than 50 m, 1·04 (1·02–1·05) for people living 50–100 m, 1·02 (1·01–1·03) for people living 101–200 m, and 1·00 (0·99–1·01) for people living 201–300 m away from a major roadway versus more than 300 m from a major roadway (Ptrend=0·0349; table 2). An interquartile-range increase in residential proximity to a major road was associated with a 9% (95% CI 8–11%) lower incidence of dementia. In contrast, there was no evidence linking traffic proximity to Parkinson's disease or multiple sclerosis (HR 1·00 for both; table 2).

Table 2
Hazard ratios and 95% CIs for the associations between residential proximity to major roadways in 1996 and the risks of incident dementia, Parkinson's disease, and multiple sclerosis in Ontario, during the follow-up period 2001–12

Table Thumbnail. Opens Table in new tab.

Cox proportional hazards model with age as the time-scale, stratified by an indicator for living in the Greater Toronto Area or not, adjusted for sex, history of diabetes, hypertension, coronary heart disease, stroke, congestive heart failure, arrhythmia, and traumatic brain injury, income quintile, urban/rural indicator, census division-level unemployment rate, education, recent immigrants, as well as the subtraction of these variables at the census dissemination level from their census division. For multiple sclerosis, the model was also adjusted for latitude.

†Major traffic roads include primary urban roads and arterial roads whereas highways include expressways and primary and secondary highways, as defined by Ontario Government Road Network Data Standards.
‡Incidence of dementia and Parkinson's disease was analysed among all adults aged 55–85 years (dementia/Parkinson's disease cohort) whereas incidence of multiple sclerosis was analysed among all adults aged 20–50 years (multiple sclerosis cohort).
§Distance was fitted as a continuous variable, using natural logarithm of distance. Hazard ratios (HRs) expressed per IQR increase in distance (dementia/Parkinson's disease cohort: 310 m and multiple sclerosis cohort: 320 m).
The association between traffic exposure and dementia was insensitive to additional controls for smoking, obesity, physical activity, and education (HR 1·06 for living <50 m away from a major road, 1·04 for 51–100 m, and 1·02 for 101–200 m; table 3). Similarly, the associations between traffic exposure and Parkinson's disease and multiple sclerosis remained unchanged after adjusting for smoking and physical activity (table 4).

Table 3
Hazard ratios and 95% CI for associations between residential proximity to major roadways in 1996 and the risk of incident dementia in Ontario during the follow-up period 2001–12

Table Thumbnail. Opens Table in new tab.

Indirect adjustment for smoking, body-mass index (BMI), physical activity, and attained education. Data of smoking, BMI, physical activity, and educational attainment were obtained from Ontario respondents to the 1996 cycle of National Population Health Survey and the 2000–01, 2003 cycles of Canadian Community Health Survey, and who were 50 to 85 years old at the time of the surveys (n=16 441).

†Major traffic roads include primary urban roads and arterial roads whereas highways include expressways and primary and secondary highways, as defined by Ontario Government Road Network Data Standards.
‡Cox proportional hazards model with age as time axis, stratified by an indicator for living in the Greater Toronto Area or not, adjusted for sex, history of diabetes, hypertension, coronary heart disease, stroke, congestive heart failure, arrhythmia, and traumatic brain injury, income quintile, urban/rural indicator, census division-level unemployment, education, and recent immigrants, as well as the subtraction of these variables at the census dissemination level from their census division.
§Distance was fitted as a continuous variable, using natural logarithm of distance. The hazard ratios were expressed per interquartile-range increase in distance (310 m).
Table 4
Hazard ratios and 95% CI for associations between residential proximity to major roadways in 1996 and risk of incident Parkinson's disease and multiple sclerosis in Ontario, during the follow-up period 2001–12

Table Thumbnail. Opens Table in new tab.

Indirect adjustment for smoking and physical activity for Parkinson's disease, and for smoking for multiple sclerosis. Data of smoking and physical activity were obtained from Ontario respondents to the 1996 cycle of National Population Health Survey and the 2000–01 and 2003 cycles of Canadian Community Health Survey. For Parkinson's disease, respondents aged 50–85 years at the time of the surveys were included (n=16 441) and for multiple sclerosis, those who were 20–55 years old were included (n=31 635).

†Major traffic roads include primary urban roads and arterial roads whereas highways include expressways and primary and secondary highways, as defined by Ontario Government Road Network Data Standards.
‡Cox proportional hazards model with age as time axis, stratified by an indicator for living in the Greater Toronto Area or not, adjusted for sex, history of diabetes, hypertension, coronary heart disease, stroke, congestive heart failure, arrhythmia, and traumatic brain injury, income quintile, urban/rural indicator, census division-level unemployment, education, and recent immigrants, as well as the subtraction of these variables at the census dissemination level from their census division. For multiple sclerosis, the model was also adjusted for latitude.
§Distance was fitted as a continuous variable, using natural logarithm of distance. HRs expressed per interquartile-range increase in distance (dementia/Parkinson's disease cohort: 310 m and multiple sclerosis cohort: 320 m).
‖For Parkinson's disease, ptrend=0·38 and for multiple sclerosis, ptrend=0·53.
Further adjustment for access to neurologists, deprivation, time trend, and a North/South indicator did not alter the associations, nor did adding a frailty term in the survival model to account for potential spatial clustering (figure 1). Adjustment for NO2 and PM2·5 modestly attenuated the association between traffic proximity and dementia (HR 1·05 for living <50 m away from a major road and HR 1·02 for 51–100 m away from a major road vs 1·07 and 1·04 without adjustment). Importantly, NO2 was significantly associated with dementia, whereas PM2·5 was associated with both dementia and Parkinson's disease (appendix).

Thumbnail image of Figure 1. Opens large image
Figure 1
Estimated associations between residential proximity to major roadways in 1996 and the risk of incident dementia, Parkinson's disease, multiple sclerosis in Ontario, 2001–12

Measured by six sensitivity analyses to further control for potential confounding factors. Model further adjusted for exposure to NO2 and PM2.5 access to neurologists, time trend, deprivation, an indicator for North/South Ontario, and a frailty term to account for potential spatial clustering.

View Large Image | View Hi-Res Image | Download PowerPoint Slide
In sensitivity analyses, the magnitude of associations were similar after further excluding the first 2 and 5 years of follow-up, restricting to people aged 65 years or older, excluding those living in long-term care facilities, or considering other sensitivity analyses (figure 2 and appendix). However, the association between living less than 50 m from a major roadway and dementia appeared stronger among participants who lived in urban areas, who lived in one of the six major cities, or who never moved (HR 1·09–1·12, depending on the analysis).

Thumbnail image of Figure 2. Opens large image
Figure 2
Association between residential proximity to major roadways in 1996 and the risk of incident dementia, Parkinson's disease, multiple sclerosis in Ontario, 2001–12

Hazard ratios and 95% CIs from six additional sensitivity analyses (excluding first 2 years of follow-up, excluding first 5 years of follow-up, excluding people living in long-term care facilities, restricting to urban residents, restricting to six major cities in Ontario, and restricting to those who did not move after 1996).

View Large Image | View Hi-Res Image | Download PowerPoint Slide
Discussion
Go
In this large population-based cohort, living near major roadways was associated with increased dementia incidence. The associations seemed stronger among urban residents, especially those living in major urban centres and those who never moved. Although the increase in risk might appear moderate (eg, HRs varied from 1·07–1·12 for living <50 m away from a major road, depending on the region), this translates to 7–11% of dementia cases in patients who live near major roads attributable to traffic exposure (appendix). The associations were robust to various sensitivity analyses, except for additional adjustment for PM2·5 and NO2 which led to a modest attenuation. It is noteworthy that both NO2 and PM2·5 were positively associated with dementia. Lastly, we found no association between roadway proximity and incidence of Parkinson's disease or multiple sclerosis.

To our knowledge, this is the first study to investigate the onset of three major neurodegenerative diseases in association with near-roadway exposure. Previous studies have linked living near roadways to cognitive decline in cohorts of older adults in Boston MA, USA18 and in the Ruhr area, Germany,19 and to smaller white matter hyperintensity volume in the Framingham Offspring cohort.17 Living near major roads substantially increases an individual's exposure to traffic-related air pollution (eg, ultrafine particles, nitrogen oxides, and particles from wear of tyres and friction materials), and noise.17 Although the mechanisms through which traffic exposure might affect brain health are unknown, systemic inflammation arising from traffic-related air pollution is probably important. In studies of both experimental animals and in autopsy samples of sudden accidental deaths in human beings, particulates and diesel exhaust provoke oxidative stress and systemic inflammatory responses, disrupt the blood-brain barrier, precipitate Aβ peptides, and activate microglia.8, 9 Ultrafine particles have also been found in the olfactory bulb and the frontal cortical areas in the brain of highly exposed dogs and human beings.8 Furthermore, emerging epidemiologic evidence relates nitrogen oxides and black carbon, markers for traffic-related pollution, to dementia incidence12 and cognitive impairment.14 We observed that exposures to NO2 and PM2·5 were related to dementia and that adjusting for these two pollutants attenuated its association with roadway proximity, suggesting that the effect of traffic exposure might, at least in part, operate through this mechanism. Given the potentially significant implications of exposure to traffic-related pollutants on dementia risk, understanding their effects merit further investigation.

The fact that PM2·5 and NO2 did not fully explain the near-road effect on dementia suggests that additional pollutants or other factors such as noise might play a role. Although we were unable to directly examine these factors, traffic-related noise has been linked to cognitive impairment in a cohort in Germany.13 In rat models, noise exposure directly impaired cognition.11 Additionally, sleep loss from noise contributes to sleep fragmentation, which is associated with reduced cognition.5 Living near busy roads might also reduce physical activity, which could subsequently affect neurological health. However, we found little change in our results after indirect adjustment for this variable.

Compared with dementia, less is known about the effect of traffic exposure on Parkinson's disease and multiple sclerosis. Only three studies have examined the relationship between traffic exposure and Parkinson's disease: a positive association between NO2 and incident Parkinson's disease was reported in a case-control study in Denmark,15 whereas in another case-control study in the USA, no association with NO2 was found.31 Additionally, in a cross-sectional study in Ontario, Parkinson's disease prevalence was not associated with roadway proximity nor NO2.32 For multiple sclerosis, one time-series study found a relationship between daily hospital admissions and particulate pollution,33 but no studies have assessed the effect of living close to traffic. In this study, we observed an association only between traffic proximity and dementia, which might be attributable to relatively few cases of Parkinson's disease and multiple sclerosis. Another possibility is that traffic exposure could augment neurodegeneration through pathways that are related to dementia but not Parkinson's disease or multiple sclerosis.3, 4, 5

Our study has some limitations. First, we could not identify undiagnosed cases of dementia, Parkinson's disease, and multiple sclerosis. However, the estimates were unchanged when we adjusted for access to neurologists, a North/South indicator, deprivation, and time trends. With universal health care in Ontario, incomplete diagnosis might lead to underestimation of the true effect because this measurement error was probably independent of the exposure.

Second, we did not have information on medications that might potentially influence dementia risk (eg, anti-inflammatory medication and NSAIDs), although it is unclear whether these factors would be associated with traffic exposure. Furthermore, we lacked information on individual socioeconomic status and behavioural variables. To control for these unmeasured variables, we adjusted for neighbourhood socioeconomic status and comorbidities. Since neighbourhood socioeconomic status is strongly associated with individual socioeconomic status and behavioural variables,25, 26 and comorbidities and neurodegenerative diseases share some common behavioural factors, adjusting for these variables should reduce the influence of these unmeasured variables on HR (appendix). We further controlled indirectly for these variables, and found similar results. Although we cannot rule out residual confounding, the null findings for Parkinson's disease and multiple sclerosis do not support this possibility.

Third, our exposure assessment was based on postal-code addresses, which do not completely reflect personal exposure. PM2·5 is a complex mixture with a secondary aerosol component that might not originate from vehicle emissions. Finally, roadway proximity does not account for traffic density and meteorological conditions that might influence exposure to air pollution and noise. Given the inherent imprecision of this exposure, our assessment of near-road exposure was probably subject to non-differential misclassification that probably attenuated our results.

The strengths of this study include the large cohorts made up of almost the entire adult population in Ontario. The many cases ascertained from validated registries enabled us to investigate fine-scale changes in traffic exposure and to examine the effect from exposures lagged up to 10 years. Our study also benefited from quantifying and comparing the effects on three major neurodegenerative diseases from traffic exposures using the same methods. Furthermore, the availability of detailed information on medical and residential history allowed us to control for important risk factors (eg, head trauma) and assess the influence of residential mobility.

Conclusions
Go
In this large cohort, living near major roadways was associated with higher incidence of dementia, but not Parkinson's disease or multiple sclerosis. Given the potentially significant implications of traffic exposure on dementia risk, understanding the effect of different aspects of traffic merits further investigation.

Contributors

HC, RTB, JCK, PJV, KT, BJM, RC, and BJ contributed to the study design. HC, ASW, and AK prepared and cleaned the data. HC, AvD, PH, and RVM contributed to the exposure assessment. RTB provided substantial scientific input in statistical methods and interpretation of the results. HC, RTB, JCK, PJV, KT, BJM, ASW, and AK contributed to the data analyses. HC took the lead in drafting the manuscript. All authors contributed to interpretation of data, provided critical revisions to the manuscript, and approved the final draft.

Declaration of interests

We declare no competing interests.

Acknowledgements

This study was supported by Public Health Ontario (PHO) and the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Parts of this material are based on data and information compiled and provided by Canadian Information Health Institute (CIHI). The opinions, results, and conclusions reported in this article do not necessarily represent the views of ICES, PHO, MOHLTC, or CIHI.

Supplementary Material
Go
Title Description Type Size
pdf iconSupplementary appendix pdf .34 MB
References
Go
Prince, M, Guerchet, M, and Prina, M. The epidemiology and impact of dementia: current state and future trends. World Health Organization, Geneva; 2015http://www.who.int/mental_health/neurology/dementia/dementia_thematicbrief_epidemiology.pdf. ((accessed June 18, 2016).)
View in Article
World Health Organization. Neurological disorders: public health challenges. World Health Organization, Geneva; 2006http://www.who.int/mental_health/neurology/neurodiso/en/. ((accessed June 18, 2016).)
View in Article
O'Gorman, C, Lucas, R, and Taylor, B. Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms. Int J Mol Sci. 2012; 13: 11718–11752
View in Article | Crossref | PubMed | Scopus (31)
Wirdefeldt, K, Adami, HO, Cole, P, Trichopoulos, D, and Mandel, J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. 2011; 26: S1–58
View in Article | Crossref | PubMed | Scopus (329)
Baumgart, M, Snyder, HM, Carrillo, MC, Fazio, S, Kim, H, and Johns, H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement. 2015; 11: 718–726
View in Article | Summary | Full Text | Full Text PDF | PubMed | Scopus (43)
Block, ML, Elder, A, Auten, RL et al. The outdoor air pollution and brain health workshop. Neurotoxicology. 2012; 33: 972–984
View in Article | Crossref | PubMed | Scopus (67)
Tzivian, L, Winkler, A, Dlugaj, M et al. Effect of long-term outdoor air pollution and noise on cognitive and psychological functions in adults. Int J Hyg Environ Health. 2015; 218: 1–11
View in Article | Crossref | PubMed | Scopus (18)
Calderon-Garciduenas, L, Solt, AC, Henriquez-Roldan, C et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults. Toxicol Pathol. 2008; 36: 289–310
View in Article | Crossref | PubMed | Scopus (201)
Block, ML, Wu, X, Pei, Z et al. Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase. FASEB J. 2004; 18: 1618–1620
View in Article | PubMed
Calderon-Garciduenas, L, Vojdani, A, Blaurock-Busch, E et al. Air pollution and children: neural and tight junction antibodies and combustion metals, the role of barrier breakdown and brain immunity in neurodegeneration. J Alzheimers Dis. 2015; 43: 1039–1058
View in Article
Cui, B, Wu, M, She, X, and Liu, H. Impulse noise exposure in rats causes cognitive deficits and changes in hippocampal neurotransmitter signaling and tau phosphorylation. Brain Res. 2012; 1427: 35–43
View in Article | Crossref | PubMed | Scopus (19)
Oudin, A, Forsberg, B, Adolfsson, AN et al. Traffic-related air pollution and dementia incidence in northern Sweden: a longitudinal study. Environ Health Perspect. 2016; 124: 306–312
View in Article
Tzivian, L, Dlugaj, M, Winkler, A et al. Long-term air pollution and traffic noise exposures and mild cognitive impairment in older adults: a cross-sectional analysis of the Heinz Nixdorf recall study. Environ Health Perspect. 2016; 124: 1361–1368
View in Article | Crossref
Power, MC, Weisskopf, MG, Alexeeff, SE, Coull, BA, Spiro, A III, and Schwartz, J. Traffic-related air pollution and cognitive function in a cohort of older men. Environ Health Perspect. 2011; 119: 682–687
View in Article | Crossref | PubMed | Scopus (104)
Ritz, B, Lee, PC, Hansen, J et al. Traffic-related air pollution and Parkinson's disease in Denmark: a case-control study. Environ Health Perspect. 2016; 124: 351–356
View in Article
Jung, CR, Lin, YT, and Hwang, BF. Ozone, particulate matter, and newly diagnosed Alzheimer's disease: a population-based cohort study in Taiwan. J Alzheimers Dis. 2015; 44: 573–584
View in Article
Wilker, EH, Preis, SR, Beiser, AS et al. Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure. Stroke. 2015; 46: 1161–1166
View in Article | Crossref | PubMed | Scopus (19)
Wellenius, GA, Boyle, LD, Coull, BA et al. Residential proximity to nearest major roadway and cognitive function in community-dwelling seniors: results from the MOBILIZE Boston Study. J Am Geriatr Soc. 2012; 60: 2075–2080
View in Article
Ranft, U, Schikowski, T, Sugiri, D, Krutmann, J, and Kramer, U. Long-term exposure to traffic-related particulate matter impairs cognitive function in the elderly. Environ Res. 2009; 109: 1004–1011
View in Article | Crossref | PubMed | Scopus (101)
Chen, H, Kwong, JC, Copes, R et al. Cohort Profile: The Ontario population health and environment cohort (ONPHEC). Int J Epidemiol. 2016;
DOI: http://dx.doi.org/10.1093/ije/dyw030
(published online April 20.)
View in Article | Crossref
Butt, DA, Tu, K, Young, J et al. A validation study of administrative data algorithms to identify patients with Parkinsonism with prevalence and incidence trends. Neuroepidemiology. 2014; 43: 28–37
View in Article | Crossref | Scopus (6)
Jaakkimainen, RL, Bronskill, SE, Tierney, MC et al. Identification of physician-diagnosed Alzheimer's disease and related dementias in population-based administrative data: a validation study using family physicians' electronic medical records. J Alzheimers Dis. 2016; 54: 337–349
View in Article | Crossref
Widdifield, J, Ivers, NM, Young, J et al. Development and validation of an administrative data algorithm to estimate the disease burden and epidemiology of multiple sclerosis in Ontario, Canada. Mult Scler. 2015; 21: 1045–1054
View in Article | Crossref | Scopus (2)
Chen, H, Goldberg, MS, Burnett, RT, Jerrett, M, Wheeler, AJ, and Villeneuve, PJ. Long-term exposure to traffic-related air pollution and cardiovascular mortality. Epidemiology. 2012; 24: 35–43
View in Article | Crossref | Scopus (41)
Janssen, I, Boyce, WF, Simpson, K, and Pickett, W. Influence of individual- and area-level measures of socioeconomic status on obesity, unhealthy eating, and physical inactivity in Canadian adolescents. Am J Clin Nutr. 2006; 83: 139–145
View in Article | PubMed
Gan, WQ, Davies, HW, Koehoorn, M, and Brauer, M. Association of long-term exposure to community noise and traffic-related air pollution with coronary heart disease mortality. Am J Epidemiol. 2012; 175: 898–906
View in Article | Crossref | PubMed | Scopus (72)
van Donkelaar, A, Martin, RV, Spurr, RJ, and Burnett, RT. High-resolution satellite-derived PM2.5 from optimal estimation and geographically weighted regression over North America. Environ Sci Technol. 2015; 49: 10482–10491
View in Article | Crossref | Scopus (13)
Hystad, P, Setton, E, Cervantes, A et al. Creating national air pollution models for population exposure assessment in Canada. Environ Health Perspect. 2011; 119: 1123–1129
View in Article | Crossref | Scopus (43)
Shin, HH, Cakmak, S, Brion, O et al. Indirect adjustment for multiple missing variables applicable to environmental epidemiology. Environ Res. 2014; 134: 482–487
View in Article | Crossref | Scopus (6)
Crouse, DL, Peters, PA, Hystad, P et al. Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the Canadian census health and environment cohort (CanCHEC). Environ Health Perspect. 2015; 123: 1180–1186
View in Article | Crossref | Scopus (13)
Liu, R, Young, MT, Chen, JC, Kaufman, JD, and Chen, H. Ambient air pollution exposures and risk of Parkinson disease. Environ Health Perspect. 2016;
DOI: http://dx.doi.org/10.1289/EHP135
(published online June 10, 2016.)
View in Article | Crossref
Finkelstein, MM and Jerrett, M. A study of the relationships between Parkinson's disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res. 2007; 104: 420–432
View in Article | Crossref | PubMed | Scopus (122)
Angelici, L, Piola, M, Cavalleri, T et al. Effects of particulate matter exposure on multiple sclerosis hospital admission in Lombardy region, Italy. Environ Res. 2016; 145: 68–73
View in Article | Crossref
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32399-6/fulltext
 

  拍手はせず、拍手一覧を見る

コメント
 
1. てんさい(い)[597] gsSC8YKzgqKBaYKigWo 2017年1月31日 09:34:34 : 0kUGInjLpY : VLecBnM2280[261]
http://biz-journal.jp/2017/01/post_17886.html
交通量の多い地域の住民、高い認知症発生率…大気中の汚染物が脳内に侵入か
文=水守啓/サイエンスライター
【この記事のキーワード】交通量, 認知症, 騒音

「Thinkstock」より

交通量と認知症


 筆者は千葉県房総半島の山の中で暮らしているが、ときどき自動車で東京湾を横切る高速道路アクアラインを通って都会に入る。湿度の低い冬は、白い雪を頂いた美しい富士山を海上から眺めることができる。だが同時に、海の向こうに見える東京・神奈川の景色は、スモッグに覆われた都会である。かつてほどではないものの、空気は汚染されている。ひとたびその環境に浸かってしまえばすぐに慣れてしまうが、都会では路上をたくさんの自動車が行き交い、騒がしい。そして、聞こえる音は、人工的なものが多く、鳥や虫の鳴き声は極めて少なくなる。

 つい先日、カナダのパブリック・ヘルス・オンタリオ(PHO)とインスティテュート・フォー・クリニカル・イバリュエイティブ・サイエンス(ICES)は、医学雑誌「ランセット」を通じて交通量の多い環境が我々の健康を脅かしているという興味深い報告を行った。研究者らは2001年から12年にかけて、20歳から85歳のオンタリオ州の住民660万人以上を調査した結果、交通量の多い道路から50メートル以内で暮らす人々は、300メートル以上離れて暮らす人々よりも7%高く認知症にかかる傾向がみられることがわかったという。

 調査によると、科学者らはオンタリオ州で認知症を24万3611件、パーキンソン病を3万1577件、多発性硬化症を9247件確認した。そして、認知症に関しては、交通量の多い環境条件との相関性を見いだすことになった。ただし、パーキンソン病と多発性硬化症に関して有意性は認められなかった。

 論文の執筆者でPHOのレイ・コープス博士によると、その結果は、多大な交通量によって生じる汚染物質が認知症と関連していることを示唆している。つまり、大気に放出された汚染物質が血流を通じて脳内に侵入し、神経性の問題につながり得ることを示唆するとしている。

 同じく、PHOの科学者ホン・チェン氏も言う。

「交通量の多い道路は、認知症の発病を高める環境ストレスの源になり得る。人口増と都市化によってますます多くの人々が激しい交通量に接し、道路に近づくだけでも身体に負担を掛け、認知症の発症率を高めている」
都会と田舎の環境ストレス


 もちろん、認知症の原因は単純なものではなく、大気汚染だけがそれを促しているわけではないだろう。たとえば、交通量の多い道路沿いには商業施設も多く、自動車以外の要素も加わった騒音も存在する。我々が耳では聞き取れない周波数帯の音や振動も発生する。それらが、近隣住民に自覚されることなくストレスを与えている可能性も考えられる。

page: 2

 騒音は、睡眠妨害をはじめ、心臓病や糖尿病をも生み出しうるが、それを不快と感じるかどうかという個人差の問題がある。その人にとって、それが不快な音であれば、騒音になり、ストレスの原因となる。一般には、そんなストレスがさまざまな症状を生み出しうると考えられている。

 だが、そもそも騒音とは音であり、波動である。波動は、不快に感じるか否かにかかわらず、電磁波同様に我々の身体に到達する。そのため、自覚できる症状が現れていなくとも、騒音はなんらかの悪影響を身体に及ぼす可能性はあり、さらなる研究は必要と思われる。

 とはいえ、環境ストレスの影響は馬鹿にならない。都会と田舎で暮らすネズミやシジュウカラを比較調査した研究においては、都会で暮らすほうが脳が発達する反面、短命であるという結果が出ており、それはヒトにも通じる可能性を示唆するものだった。

 独ハイデルベルグ大学のメンタルヘルス中央研究所は、2011年の研究で、都市生活者のほうが脳へのストレスが大きいことを明らかにして、イギリスの科学誌「ネイチャー」に発表している。ポーランドの「プシェクルイ」誌も、都市生活者は田舎暮らしの人々よりも、不安障害が21%、気分障害(うつ病)が39%も高い確率でかかると分析報告している。また、2005年の調査報告において、都市部で育った人が統合失調症にかかる確率は田舎暮らしの2倍というものもあった。

 そう考えると、交通量の多い道路の近くで暮らす人々は、直接的に空気中の汚染物質の影響を受けるだけでなく、都会に特有の環境ストレスにも曝されていることになる。

 都会では、さまざまな職の機会に恵まれ、所得の高い人々が多く、高学歴にもつながるだけでなく、便利さといったメリットも多い。だが、その反面、空気中の汚染物質を体内に取り込み、騒音という波動を浴び、ストレスを抱える機会も増えることになる。今後、我々は目先と将来のことを考え、両者を天秤にかけて生活の場を選ぶ自覚が求められるのかもしれない。
(文=水守啓/サイエンスライター)

【参考記事】
Living close to busy roads may cause dementia − study(RT)
「都会」と「田舎」でこれだけ違う<脳ストレス>(HEALTH PRESS)

●水守 啓(ケイ・ミズモリ)
「自然との同調」を手掛かりに神秘現象の解明に取り組むナチュラリスト、サイエンスライター、リバース・スピーチ分析家。 現在は、千葉県房総半島の里山で農作業を通じて自然と触れ合う中、研究・執筆・講演活動等を行っている。著書に『底なしの闇の[癌ビジネス]』(ヒカルランド)、『超不都合な科学的真実』、『超不都合な科学的真実 [長寿の秘密/失われた古代文明]編』『宇宙エネルギーがここに隠されていた』(共に徳間書店)、 『リバース・スピーチ』(学研プラス)、『聖蛙の使者KEROMIとの対話』『世界を変えるNESARAの謎』(共に明窓出版)などがある。
ホームページ: http://www.keimizumori.com/


  拍手はせず、拍手一覧を見る

フォローアップ:


★登録無しでコメント可能。今すぐ反映 通常 |動画・ツイッター等 |htmltag可(熟練者向)|(各説明

←ペンネーム新規登録ならチェック)
↓ペンネーム(なしでも可能。あったほうが良い)

↓パスワード(ペンネームに必須)

(ペンネームとパスワードは初回使用で記録、次回以降にチェック。パスワードはメモすべし。)
↓画像認証
( 上画像文字を入力)
ルール確認&失敗対策
画像の URL (任意):
最新投稿・コメント全文リスト  コメント投稿はメルマガで即時配信  スレ建て依頼スレ

▲上へ      ★阿修羅♪ > 不安と不健康18掲示板 次へ  前へ

★阿修羅♪ http://www.asyura2.com/ since 1995
スパムメールの中から見つけ出すためにメールのタイトルには必ず「阿修羅さんへ」と記述してください。
すべてのページの引用、転載、リンクを許可します。確認メールは不要です。引用元リンクを表示してください。
 
▲上へ       
★阿修羅♪  
不安と不健康18掲示板  
次へ